PROJECT SUMMARY This proposal requests funds that will be used in combination with funds provided by the Ludwig Institute for Cancer Research (LICR) to purchase an Orbitrap Fusion mass spectrometer (MS) to empower the research projects of biomedical research investigators at the University of California at San Diego (UCSD) School of Medicine, including those also affiliated with the San Diego Branch of the LICR. The requested Orbitrap Fusion MS has greatly improved technical capabilities in throughput, accuracy and sensitivity, thus providing a major upgrade from the existing and ageing mass spectrometers that have been supporting proteomics research at UCSD and the LICR for the past fourteen years. The Thermo Orbitrap Fusion MS is an indispensible tool for cutting edge proteomics research, and currently, there is no such instrument on the UCSD campus. Our user group consists of both basic and clinical scientists working on a wide range of projects in (a) cancer genetics, DNA repair and genome instability (Kolodner, Zhou and Putnam), (b) aneuploidy and birth defects (Corbett, Desai and Hollingsworth), (c) glioblastoma and drug resistance mechanisms in cancer (Furnari and Mischel), (d) cancer biology (Wang, Fu, Guan and Field), (d) genomics and chromatin organization (Ren) and (e) neurodegeneration (Cleveland). All of the user projects involve characterization of protein-nucleic acid and protein-protein associations as well as various post- translational protein modifications in both normal and diseased tissues and cells. The application of quantitative proteomics implemented with the proposed Orbitrap Fusion MS is essential to the success of the research projects presented in this application. The proposed Orbitrap Fusion MS, with its superior technical capabilities, will allow us to investigate physiological and pathological processes with improved precision and to generate new insights relevant to the diagnosis and treatment of human diseases.